HIV infection is associated with massive loss of memory CD4 T cells in mucosal tissues such as the gastrointestinal and oral mucosa. These CD4 T cells not only serve as a pool of readily available target cells for propagating HIV infection but are also critical for the generation of anti-viral CD8 T cell responses against previously exposed and opportunistic pathogens. Limited information exists regarding the ability of mucosal vaccination to protect the CD4 T cell compartment in mucosal sites. Recent studies have demonstrated that systemic vaccination induced suboptimal mucosal immune responses that were associated with partial protection of the mucosal CD4 T cells. Given the highly compartmentalized nature of the mucosal immune system it is highly likely that mucosal vaccination can induce stronger immune responses in mucosal tissues than systemic vaccination. The overall objectives of this proposal are to evaluate mucosal vaccination strategies to induce potent immune responses in the mucosa. We hypothesize that mucosal vaccination can induce potent immune responses that can better protect the CD4 T cells in the mucosa after challenge, and this protection will correlate with better long-term outcome. We propose to test this hypothesis using the rhesus macaque model. In Specific aim 1 we will determine if systemic prime/mucosal boost can significantly amplify mucosal immune responses better than systemic boosting. In Specific aim 2 we will determine if alternate mucosal vaccination routes are better at inducing potent immune responses in the mucosa. In Specific aim 3 we propose to vaccinate mucosally with adjuvants to determine if it can potentiate immune responses in the mucosa that better correlate with protection. Overall these studies will allow us to delineate the role of vaccine induced mucosal immunity in protecting the mucosa CD4 T cell compartment from infection leading to better long-term outcome. PUBLIC HEALTH RELEVANCE: HIV causes immunodeficiency very rapidly by killing the cells it infects. Protecting these cells from infection is critical to prevent the devastating effect of HIV infection and the onset of secondary infections. This project explores the role of mucosal vaccination in protecting cells from getting infected with HIV thereby leading to a better long-term survival outcome. The studies proposed here will aid in the development of an effective vaccine against HIV.